Plant polyphenols exhibit potentially useful effects in a wide variety of pathophysiological settings. They interact with proteins
such as signalling kinases, transcription factors and ion channels, and modulate redox processes, such as those taking place in
mitochondria. Biomedical applications of these natural compounds are however severely hindered by their low bioavailability, rapid
metabolism, and often by unfavourable physico-chemical properties, e.g. a generally low water solubility. Derivatives are under
development with the aim of improving their bioavailability and/or bioefficacy. Various strategies can be adopted. An increase in
circulating blood levels of non-metabolized natural compound may be attainable through prodrugs. In the ideal prodrug, phenolic
hydroxyls are protected by capping groups which a) help or at least do not hinder permeation of epithelia; b) prevent conjugative
modifications during absorption and first-pass through the liver; c) are eliminated with opportune kinetics to regenerate the parent
compound. Moreover, prodrugs may be designed with the goals of modulating physical properties of the parent compound, and/or
changing its distribution in the body. A more specific action may be achieved by concentrating the compounds at specific sites of action.
An example of the second approach is represented by mitochondria-targeted redox-active polyphenol derivatives, designed to intervene
on radical processes in these organelles and as a tool either to protect cells from oxidative insults or to precipitate their death.
Mitochondrial targeting can be achieved through conjugation with a triphenylphosphonium lipophilic cation. Quercetin and resveratrol
were chosen as model polyphenols for these proof-of-concept studies. Data available at the moment show that both quercetin and
resveratrol mitochondria-targeted derivatives are pro-oxidant and cytotoxic in vitro, selectively killing fast-growing and tumoural cells
when supplied in the low μM range; the mechanism of ROS generation appears to differ between the two classes of compounds.
These approaches are emerging as promising strategies to obtain new efficient chemopreventive and/or chemotherapeutic drugs based on
Keywords: Bioavailability, catechins, mitochondria, polyphenols, prodrugs, quercetin, resveratrol, triphenylphosphonium.
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